WO2008133884A2 - Procédés et compositions pour traiter des maladies neurodégénératives - Google Patents

Procédés et compositions pour traiter des maladies neurodégénératives Download PDF

Info

Publication number
WO2008133884A2
WO2008133884A2 PCT/US2008/005194 US2008005194W WO2008133884A2 WO 2008133884 A2 WO2008133884 A2 WO 2008133884A2 US 2008005194 W US2008005194 W US 2008005194W WO 2008133884 A2 WO2008133884 A2 WO 2008133884A2
Authority
WO
WIPO (PCT)
Prior art keywords
agent
agents
group
composition
tables
Prior art date
Application number
PCT/US2008/005194
Other languages
English (en)
Inventor
Xiaowei Jin
Jane Staunton
Douglas Macdonald
Hualing Dong
Lydia Kifle
Original Assignee
Combinatorx, Incorporated
Chdi, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Combinatorx, Incorporated, Chdi, Inc. filed Critical Combinatorx, Incorporated
Publication of WO2008133884A2 publication Critical patent/WO2008133884A2/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • this invention relates to the treatment, prevention, and amelioration of neurodegenerative disorders, e.g., Huntington's disease, and symptoms thereof.
  • Neurodegenerative disorders affect millions of individuals.
  • One class of these disorders, the polyglutamine expansion disorders is characterized by the presence of an expanded CAG repeat region within the coding sequence of a gene. While the threshold length of the CAG expansion is variable in these disorders, longer repeat length generally results in an earlier onset of the disease.
  • the threshold CAG repeat length for the onset of the disease is generally regarded as greater than 38 CAGs, resulting in a polyglutamine domain proximal to the N-terminus of the Huntingtin protein.
  • Huntington's disease one of at least nine known inherited polyglutamine expansion disorders, affects men and women with equal frequency, about 5-10 per 100,000. It can be characterized by five hallmark features: heritability; chorea; behavioral or psychiatric disturbances; cognitive impairment (dementia); and late-onset, with death occurring 15-20 years post- onset of motor dysfunctions. In most patients, the onset of the disease occurs in the third to fifth decade of life.
  • HD is an autosomal dominant disorder with a gene mutation on chromosome 4. This gene encodes a large protein, huntingtin (Htt), with multiple important functions. HD is caused by an expansion of the CAG repeat in the huntingtin (htt) gene, resulting in an expanded polyglutamine (poly Q) region near the N-terminus of Htt.
  • htt huntingtin
  • poly Q polyglutamine
  • HD pathologic mechanisms underlying HD are not yet completely understood.
  • Leading hypotheses include excitotoxicity, mitochondrial dysfunction, deficiencies in ubiquitin-mediated proteolysis, protease-dependent accumulation of poly-glutamine protein fragments, formation of cytosolic and nuclear inclusions, changes in gene expression, and neuronal cell degeneration and death.
  • apoptosis plays an important role.
  • There are no current HD therapies although some patients treat their symptoms with conventional neuroleptics to decrease chorea, and psychotropic medications to address depression, obsessive compulsive symptoms, or psychosis.
  • compositions, methods, and kits for treating, preventing, and ameliorating neurodegenerative disorders may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, such as HD.
  • the compositions, methods, and kits described herein also may be useful for treating symptoms or complications associated with neurodegenerative disorders, e.g., chorea, depression, obsessive-compulsive behavior, psychosis, dystonia (e.g., jaw clenching), and behavioral disturbances.
  • compositions that includes one or more first agents selected independently from the agents of Tables Ia and Ib, and one or more second, different agents selected independently from the classes and agents of Tables Ia, Ib, and 2.
  • the agent or agents of Tables Ia and Ib can be, e.g., tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, selective serotonin reuptake inhibitors ("SSRIs”), anticholinergics, IKK- ⁇ inhibitors, or estrogen modulators.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first agent and second agent are present in amounts that, when administered to a patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder, e.g., a disorder selected from the group consisting of a polyglutamine expansion disorder (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), another trinucleotide repeat expansion disorder (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Bat
  • compositions consisting of active ingredients and pharmaceutically acceptable carriers, wherein the active ingredients consist of a first agent selected independently from the agents of Tables Ia and Ib, and a second, different agent selected independently from the classes and agents of Tables Ia, Ib, and 2.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first and second agents may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other.
  • the agent or agents administered to the patient may reduce the rate of neuronal death in the patient (e.g., a human) relative to the rate of neuronal death in a control.
  • the methods may include an additional therapeutic regimen.
  • the additional therapeutic regimen may include administering to the patient an additional therapeutic agent, such that the agent or agents selected from Tables Ia and Ib and the additional therapeutic agent are present in amounts that, when administered to the patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder.
  • the additional therapeutic agent may be, e.g., selected from the classes and agents of Table 2.
  • the agent or agents from Tables Ia or Ib and the additional therapeutic agent may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other, via any route of administration.
  • kits that includes an agent selected from the agents of Tables Ia and Ib and instructions for administering the agent to a patient having or at risk of having a neurodegenerative disorder.
  • the kit includes two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib that may, but need not be, admixed in the same composition.
  • This kit may also include instructions for administering the additional agent or agents, or the admixed composition, to the patient.
  • kits that includes one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib and one or more agents selected independently from the classes and agents of Table 2.
  • the agents may, but need not, be admixed in the same composition.
  • the kit also includes instructions for administering these agents to a patient having or at risk of having a neurodegenerative disorder.
  • kits that includes either one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib, or one or more agents selected independently from the classes and agents of Table 2.
  • the kit also includes instructions for administering these agents together to a patient having or at risk of having a neurodegenerative disorder.
  • two agents may be selected from a single row of Tables 3a and 3b.
  • Also provided is a method of identifying a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder including the steps of: (a) providing cells that include a gene encoding a polyglutamine repeat polypeptide, such that the polypeptide includes an expanded polyglutamine repeat region relative to a wild-type polyglutamine repeat polypeptide; (b) inducing expression of the gene; (c) contacting the cells with an agent selected from the agents of Tables Ia and Ib and a candidate compound; and (d) determining whether the combination of the agent and the candidate compound reduces perinuclear staining by a polyQ antibody, e.g., 1F8, relative to cells contacted with the agent but not contacted with the candidate compound, wherein a reduction in perinuclear staining (as determined, e.g., by immunocytochemistry (ICC) analysis) identifies the combination as a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder.
  • the polyglutamine repeat polypeptide that includes the expanded polyglutamine repeat region may include, e.g., full-length Htt Ql 11, or another variant of a polypeptide associated with a polyglutamine expansion disorder.
  • the method may use, e.g., mammalian cells, e.g., mouse striatal cells, e.g., STHdhQl 11 cells derived from knock- in mice.
  • an amount sufficient is meant the amount of a compound, alone or in combination with another therapeutic regimen, required to treat, prevent, or ameliorate a neurodegenerative disorder, such as HD, in a clinically relevant manner.
  • a sufficient amount of an active compound used for therapeutic treatment of neurodegenerative disorders varies depending upon the manner of administration, age, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of compound in the combination that is safe and efficacious in the treatment of a patient having a neurodegenerative disorder, such as HD, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug
  • Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
  • Compounds include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.
  • Compounds may also be isotopically labeled compounds.
  • Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl).
  • Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non- isotopically-labeled reagent.
  • expanded polyglutamine repeat region is meant a region of a polyglutamine repeat polypeptide in which the number of glutamine residues is greater than the number of glutamine residues in a corresponding wild-type polypeptide.
  • An exemplary polypeptide containing an expanded polyglutamine repeat region is, e.g., full-length HttQl 11, which contains a region of 111 glutamine residues.
  • An expanded polyglutamine repeat region contains greater than, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or even 100 glutamine residues.
  • an expanded polyglutamine repeat region contains greater than, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
  • a high dosage is meant at least 5% more (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • a high dosage of an agent that prevents or slows the rate of neural deterioration or death associated with a neurodegenerative disorder and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • neurodegenerative disorder any disease or disorder caused by or associated with the deterioration of cells or tissues of the nervous system.
  • exemplary neurodegenerative disorders are polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-S
  • patient any animal, e.g., a mammal (e.g., a human).
  • Other animals that can be treated using the methods, compositions, and kits described herein include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • a patient who is being treated for a neurodegenerative disorder is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein. A patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • a neurodegenerative disorder e.g., HD
  • a patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • patients may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age, family history of neurodegenerative disorders, and psychological or psychiatric profile.
  • polyglutamine repeat polypeptide is meant any polypeptide containing at least five consecutive glutamine residues.
  • Exemplary polyglutamine repeat polypeptides are those associated with polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)).
  • polyglutamine expansion disorders e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)
  • Htt which is associated with HD, is a polyglutamine repeat polypeptide.
  • polypeptide and “peptide” are used interchangeably and refer to any chain of more than two natural or unnatural amino acids, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally-occurring or non-naturally occurring polypeptide or peptide, as is described herein.
  • a natural amino acid is a natural ⁇ -amino acid having the L-conf ⁇ guration, such as those normally occurring in natural proteins.
  • Unnatural amino acid refers to an amino acid, which normally does not occur in proteins, e.g., an epimer of a natural ⁇ -amino acid having the L configuration, that is to say an amino acid having the unnatural D- configuration; or a (D,L)-isomeric mixture thereof; or a homologue of such an amino acid, for example, a ⁇ -amino acid, an ⁇ , ⁇ -disubstituted amino acid, or an ⁇ -amino acid wherein the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms, such as an ⁇ - amino alkanoic acid with 5 up to and including 10 carbon atoms in a linear chain, an unsubstituted or substituted aromatic ( ⁇ -aryl or ⁇ -aryl lower alkyl), for example, a substituted phenylalanine or phenylglycine.
  • an amino acid side chain has been shortened by one or two methylene groups or lengthened
  • systemic administration is meant any nondermal route of administration, and specifically excludes topical and transdermal routes of administration.
  • treating, preventing, or ameliorating a neurodegenerative disorder is meant ameliorating such a condition before or after its onset. As compared with an equivalent untreated control, such amelioration or degree of prevention is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 6 carbon atoms or Ci-C 6 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range.
  • an alkyl group from 1 to 6 carbon atoms includes each Of C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 .
  • a CpCi 2 heteroalkyl for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl.
  • Cyclic groups can be monocyclic or polycyclic and, in some embodiments, have from 3 to 6 ring carbon atoms, inclusive.
  • Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • C 1 -C 6 alkyl is meant a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms.
  • a C 1 -C 6 alkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 1 -C 6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
  • C 2 -C 6 alkenyl is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms.
  • a C 2 -C 6 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members.
  • the C 2 -C 6 alkenyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2 -C 6 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-l-ethenyl, 1-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, and 2-methyl-2-propenyl.
  • C 2 -C 6 alkynyl is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms.
  • a C 2 -C 6 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the C 2 - C 6 alkynyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2 -C 6 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, and 3-butynyl.
  • C 2 -C 6 heterocyclyl is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom.
  • a nitrogen atom in the heterocycle may optionally be quaternized.
  • Heterocycles include, without limitation, lH-indazole, 2-pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH- carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-
  • 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH- indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.
  • 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
  • C 6 -Ci 2 aryl is meant an aromatic group having a ring system comprised of carbon atoms with conjugated ⁇ electrons (e.g., phenyl).
  • the aryl group has from 6 to 12 carbon atoms.
  • Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the aryl group may be substituted or unsubstituted.
  • substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  • C 7 -Ci 4 alkaryl is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
  • C 3 -Ci 0 alkheterocyclyl is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2- tetrahydrofuranylmethyl).
  • Ci-C 7 heteroalkyl is meant a branched or unbranched alkyl, alkenyl, or alkyny 1 group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P.
  • Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides.
  • a heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the heteroalkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • Ci-C 7 heteroalkyls include, without limitation, methoxymethyl and ethoxy ethyl.
  • halogen is meant bromine, chlorine, iodine, or fluorine.
  • fluoroalkyl is meant an alkyl group that is substituted with a fluorine atom.
  • perfluoroalkyl is meant an alkyl group consisting of only carbon and fluorine atoms.
  • carboxyalkyl is meant a chemical moiety with the formula
  • R is selected from C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C 12 aryl, C 7 -C 14 alkaryl, C 3 -Cj 0 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • hydroxyalkyl is meant a chemical moiety with the formula -(R)- OH, wherein R is selected from C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 - C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • alkoxy is meant a chemical substituent of the formula -OR, wherein R is selected from CpC 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, and Ci-C 7 heteroalkyl.
  • aryloxy is meant a chemical substituent of the formula -OR, wherein R is a C 6 -C 12 aryl group.
  • alkylthio is meant a chemical substituent of the formula -SR, wherein R is selected from Ci -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -Ci 4 alkaryl, C 3 -C] 0 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • arylthio is meant a chemical substituent of the formula -SR, wherein R is a C 6 -Ci 2 aryl group.
  • quaternary amino is meant a chemical substituent of the formula
  • R, R', R", and R'" are each independently an alkyl, alkenyl, alkynyl, or aryl group.
  • R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety.
  • the nitrogen atom, N is covalently attached to four carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.
  • compositions, methods, and kits described herein may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, e.g., HD. Accordingly, a patient that has been diagnosed with or is at risk of having a neurodegenerative disorder is administered one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib. Optionally, analogs of these agents may be employed. In the case of a polyglutamine expansion disorder, for example, such administration may prevent or slow the rate of neural deterioration or death.
  • the ability of the agent to prevent or slow the rate of neural deterioration or death may be attributed, for example, to its ability to inhibit the disease-causing activity of a mutant polyglutamine protein, e.g., Htt.
  • the patient may also receive other therapeutic regimens.
  • the patient being treated is administered two agents selected independently from any of the agents of Tables Ia and Ib within 28 days of each other in amounts that together are sufficient to treat, prevent, or ameliorate the neurodegenerative disorder.
  • the two agents are desirably administered within 14 days of each other, more desirably within seven days of each other, and even more desirably within twenty- four hours of each other, or even simultaneously. If desired, either one of the two agents may be administered in low dosage.
  • the methods and compositions described herein may be useful for treating any patient that has been diagnosed with or is at risk of having a neurodegenerative disorder, such as HD.
  • a patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • a patient may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • Diagnosis of neurodegenerative disorders, e.g., HD may be performed using any standard method known in the art, such as those described herein. Methods for diagnosing such disorders are described, for example, in U.S. Patent Nos. 6,355,481 and 6,210,970.
  • HD may be diagnosed and monitored, for example, by performing genetic tests (e.g., by sequencing the htt gene and testing for the presence of an expanded CAG repeat region); neurological examination, e.g., testing body movement, reflexes, eye movement, hearing, or balance, and/or performing brain imaging; evaluating family history of disease; or conducting a psychological or psychiatric interview.
  • Symptoms or altered behavior that can lead to a diagnosis of HD include, e.g., aggression, altered sexuality, anxiety, apathy, delusions, denial, depression, disinhibition, frustration, hallucinations, irritability, mania, repetition, and lack of awareness.
  • a patient may be diagnosed as having or being at risk of having HD if a genetic test is performed and the number of CAG repeats in the htt gene is greater than a threshold number, e.g., 38. A larger number of repeats is generally associated with an earlier onset of disease. Similar diagnostic methods may be used, e.g., for any of the polyglutamine expansion disorders. In addition, genetic, neurological, and/or behavioral testing may be used to diagnose other neurodegenerative disorders. Therapeutic Agents
  • An effective amount of one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib may be administered to a patient having, or being at risk of having, a neurodegenerative disorder, thereby treating, preventing, or ameliorating such a disorder.
  • an agent described herein may inhibit the disease-causing activity of a mutant Htt protein, e.g., by preventing or reducing Htt aggregation.
  • compositions, methods, and kits described herein include tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, SSRIs, anticholinergics, EKK- ⁇ inhibitors, and estrogen modulators, as described in more detail below.
  • Tricyclic antidepressants generally work by inhibiting the re- uptake of neurotransmitters, such as norepinephrine, dopamine, or serotonin, by nerve cells. TCAs may be used to treat neurodegenerative disorders.
  • TCAs that may be suitable for use in the compositions, kits, and methods described herein include, e.g., amoxapine, amitriptyline, BTCP hydrochloride, clomipramine (e.g., clomipramine hydrochloride), desipramine, dothiepin, doxepin, duloxetine, fluoxetine hydrochloride, fluvoxamine maleate, 7- hydroxyamoxapine, 8-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, lofepramine, loxapine (e.g., loxapine succinate, loxapine hydrochloride), maprotiline hydrochloride, norfluoxetine, nortriptyline (e.g., nortriptyline hydrochloride), paroxetine hydrochloride, protriptyline, sertraline hydrochloride, and trimipramine.
  • clomipramine e.g., clomi
  • Nortriptyline has the structure:
  • Exemplary analogs of nortriptyline are amitriptylin, amoxapine, butriptyline, clomipramine, dothiepin, doxepin, desipramine, 8- hydroxyamoxapine, 7-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, iprindole, lofepramine, loxapine, loxapine succinate, loxapine hydrochloride, maprotiline, mianserin, octriptyline, opipramol, oxaprotiline, protriptyline, trimipramine, and pharmaceutically acceptable salts thereof (described, e.g., in U.S.
  • Patent Nos. 4,933,438 and 4,931,435) which are tricyclic antidepressants or act by blocking neuroepinephrine transport. Analogs of nortriptyline are also described by Formula PP in U.S. Application Publication No. 2005- 0080265.
  • Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and survival of cells, and thus have antibiotic properties.
  • Ionophore antibiotics may be used to treat neurodegenerative disorders.
  • Ionophore antibiotics that may be suitable for use in the compositions, kits, and methods described herein include, e.g., alborixin, antibiotic A204, antibiotic X206, antibiotic A32887, antibiotic X-14766A, beauvericin, calcimycine (also referred to as A23187), calixarene, CCCP, chlorogenic acid, Compound 47,224, Compound 51,532, crown ether, dianemycin, dinactin, 2,4-dinitrophenol, NjN-dioctadecylmethylamine (also referred to as Proton ionophore III), etheromycin, FCCP, gramicidin A, grisorixin, ionomycin, isolasalocid A, K41, lasaloci
  • Analogs of Maduramicin include the other polyether antiobiotics named above.
  • Cannabinoid Agonists include a group of substances that are structurally related to THC or that bind to cannabinoid receptors (e.g., diterpene C21 compounds present in Cannabis sativa L). Cannabinoid agonists may be used to treat neurodegenerative disorders.
  • Cannabinoid agonists that may be suitable for use in the compositions, kits, and methods described herein include, e.g., ajulemic acid (IP-751), CP-55940, HU210, SR141716, SR144528, WIN 55,212-2, JWH-133, nabilone, levonantradol, marinol, sativex, tetrahydrocannabinol (THC), and analogs thereof.
  • WIN 55,212-2 has the following structure:
  • Analogs of WIN 55,212-2 include ligands and modulators of the CBl receptor and include: SR 141716A; Formulas (II) and (III) in U.S. Patent No. 6,825,209; Formulas (I) and (II) in U.S. Patent No. 5,596,106; and Formula (I) in U.S. Patent No. 6,509,367.
  • Channel Blockers are compounds, ranging from ions to complex organic molecules, that block the flow of ions through an ion channel. Channel blockers may be used to treat neurodegenerative disorders. Channel blockers that may be suitable for use in the compositions, kits, and methods described herein include, e.g., calcium channel blockers and sodium channel blockers.
  • Calcium channel blockers include, e.g., dihydropyridines (e.g., amlodipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine; nicardipine; nifedipine; nimodipine; nisoldipine; and nitrendipine); phenylalkylamines (e.g., gallopamil and verapamil); benzodiazepines (e.g., diltiazem); and other agents, e.g., BAPTA-AM; bepridil; magnesium; and menthol; and paramethadione.
  • dihydropyridines e.g., amlodipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine; nicardipine; nifedipine; nimodipine
  • Sodium channel blockers include, e.g., dibucaine (e.g., dibucaine hydrochloride); disopryamide; dyclonine (e.g., dyclonine hydrochloride); flecainide; lidocaine; mexiletine; moricizine; phenytoin; procainamide; propafenone; quinidine (e.g., quinidine gluconate); and tocainide.
  • Additional channel blockers that may be useful include, e.g., levetiracetam.
  • Bepridil has the following structure:
  • Antihistamines are compounds that block the action of histamine.
  • Antihistamines may be used to treat neurodegenerative disorders.
  • Classes of antihistamines include:
  • Ethanolamines e.g., bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine
  • Ethylenediamines e.g., pheniramine, pyrilamine, tripelennamine, and triprolidine
  • Phenothiazines e.g., diethazine, ethopropazine, methdilazine (e.g., methdilazine hydrochloride), promethazine, thiethylperazine, and trimeprazine
  • Alkylamines e.g., acrivastine, brompheniramine, chlorpheniramine, desbrompheniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine
  • Piperazines e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine
  • Piperidines e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine
  • Piperazines e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine
  • Piperidines e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine
  • Atypical antihistamines e.g., azelastine, levocabastine, methapyrilene, and phenyltoxamine.
  • nonsedating and sedating antihistamines may be employed.
  • Exemplary antihistamines that may be used in the methods, compositions, and kits described herein are non-sedating antihistamines such as loratadine and desloratadine. Sedating antihistamines may also be used in the methods, compositions, and kits described herein.
  • Exemplary sedating antihistamines of the methods, compositions, and kits described herein are azatadine, bromodiphenhydramine; chlorpheniramine; clemizole; cyproheptadine (e.g., cyproheptadine hydrochloride); dimenhydrinate; diphenhydramine; doxylamine; meclizine; promethazine (e.g., promethazine hydrochloride); pyrilamine; thiethylperazine; and tripelennamine.
  • azatadine bromodiphenhydramine
  • chlorpheniramine clemizole
  • cyproheptadine e.g., cyproheptadine hydrochloride
  • dimenhydrinate diphenhydramine
  • doxylamine meclizine
  • promethazine e.g., promethazine hydrochloride
  • pyrilamine thiethylperazine
  • antihistamines that may be suitable for use in the methods, compositions, and kits described herein are acrivastine; ahistan; antazoline (e.g., antazoline phosphate); astemizole; azelastine (e.g., azelsatine hydrochloride); bamipine; bepotastine; bietanautine; brompheniramine (e.g., brompheniramine maleate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; chloropyramine; chlorothen; chlorphenoxamine; cinnarizine; clemastine (e.g., clemastine fumarate); clobenzepam; clobenztropine; clocinizine; cyclizine (e.g., cyclizine hydrochloride; cyclizin
  • Antihistamine analogs include, without limitation, 10-piperazinylpropylphenothiazine; 4-(3- (2-chlorophenothiazin- 10-yl)propyl)- 1 -piperazineethanol dihydrochloride; 1 - ( 10-(3 -(4-methy 1- 1 -piperaziny l)propy I)- 1 OH-phenothiazin-2-y 1)-(9CI) 1 - propanone; 3-methoxycyproheptadine; 4-(3-(2-Chloro-10H-phenothiazin-10- yl)propyl)piperazine-l-ethanol hydrochloride; 10,1 l-dihydro-5-(3-(4- ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H- dibenzo(a,d)cycloheptene; aceprometazine;
  • DF-1111301 ; EL-301; elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine; levoprotiline; metoclopramide; NIP-531; noberastine; oxatomide; PR-881-884A; quisultazine; rocastine; selenotifen;
  • UCB-35440 VUF-K-8707; Wy-49051; and ZCR-2060.
  • Clemastine has the following structure:
  • Exemplary clemastine analogs include: N-methy 1-2- [2 '-(p- chlorobenzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2' -benzyhy dry loxy)- ethyl]-piperidine; N-methyl-2-[2'-(p-bromo-benzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2 ' -(p-fluoro-benzhy dry loxy )-ethy 1] -piperidine; N-methy 1-2- [2 ' - (p-methyl-benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(p- methoxyzbenzhydryloxy) ethyl]-piperidine; N-methy 1-2- [2'- ( -methyl- benzhydryloxy)-ethyl]-
  • Cyproheptadine has the following structure:
  • R 1 , R 2 , R 3 , R 4 , K 5 , R 6 , R 7 , and Rg are each selected from H, C 1-6 alkyl, perhalogenated C 1-6 alkyl, OH, OCi -6 alkyl, OCF 3 , SH, SC 1 .
  • Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S;
  • A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive;
  • R 9 is H or Ci -6 alkyl;
  • B 1 and B 2 are selected from H, perhalogenated C 1-6 alkyl, Ci -6 alkyl, or B 1 and B 2 , B 1 and R 9 , or B 2 and R 9 join together to form an optionally substituted ring.
  • Suitable SSRIs may include amoxapine; BTCP (e.g., BTCP hydrochloride); cericlamine (e.g., cericlamine hydrochloride); citalopram (e.g., citalopram hydrobromide); clovoxamine; cyanodothiepin; dapoxetine; dothiepin; duloxetine; escitalopram (escitalopram oxalate); femoxetine (e.g., femoxetine hydrochloride); fenfluramine (e.g., fenfluramine hydrochloride); fluoxetine (e.g., fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride
  • Cericlamine Cericlamine has the following structure:
  • Structural analogs of cericlamine are those having the formula:
  • R 1 is a C 1 -C 6 alkyl and R 2 is H or Q-C 6 alkyl
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 cyclic carbon atoms, alkanoyl, phenylalkanoyl or cycloalkylcarbonyl having 3 to 6 cyclic carbon atoms, or R 2 and R 3 form, together with the nitrogen atom to which they are linked, a heterocycle saturated with 5 to 7 chain links which can have, as the second heteroatom not directly connected to the nitrogen atom, an oxygen, a sulphur or a nitrogen, the latter nitrogen heteroatom possibly carrying a C 2 -C 6 alkyl.
  • cericlamine structural analogs are 2-methyl-2-amino-3-(3,4- dichlorophenyl)-propanol, 2-pentyl-2-amino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2-methylamino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2- dimethylamino-3-(3,4-dichlorophenyl)-propanol, and pharmaceutically acceptable salts of any thereof. Citalopram
  • Citalopram has the following structure:
  • Structural analogs of citalopram are those having the formula:
  • each Of R 1 and R 2 is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, cyano and R-CO-, wherein R is C 1 -C 6 alkyl.
  • Exemplary citalopram structural analogs are l-(4'-fluorophenyl)-l-(3-dimethylaminopropyl)-5- bromophthalane; l-(4'-chlorophenyl)-l-(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -
  • Clovoxamine has the following structure:
  • Structural analogs of clovoxamine are those having the formula:
  • Hal is a chloro, bromo, or fluoro group and R is a cyano, methoxy, ethoxy, methoxy methyl, ethoxymethyl, methoxyethoxy, or cyanomethyl group.
  • Exemplary clovoxamine structural analogs are 4'-chloro-5- ethoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- methoxycaprophenone O-(2-aminoethyl)oxime; 4'-chloro-6- ethoxycaprophenone O-(2-aminoethyl)oxime; 4'-bromo-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- methoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- cyanocaprophenone O-(2-aminoethyl)oxime; 4'-chloro-5-cyanovalerophenone O
  • Femoxetine has the following structure:
  • Structural analogs of femoxetine are those having the formula:
  • Ri represents a Ci-C 6 alkyl or C 2 -C 6 alkynyl group, or a phenyl group optionally substituted by C 1 -C 6 alkyl, CpC 6 alkylthio, CpC 6 alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, or tetrahydronaphthyl
  • R 2 represents a C 1 -C 6 alkyl or C 2 -C 6 alkynyl group
  • R 3 represents hydrogen, C 1 -C 6 alkyl, C]-C 6 alkoxy, trifluoroalkyl, hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy.
  • Fluoxetine has the following structure:
  • Structural analogs of fluoxetine are those compounds having the formula:
  • each R 1 is independently hydrogen or methyl; R is naphthyl or
  • each of R 2 and R 3 is, independently, bromo, chloro, fluoro, trifluoromethyl, Q-C 6 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 alkenyl; and each of n and m is, independently, 0, 1 or 2.
  • R is naphthyl, it can be either ⁇ -naphthyl or ⁇ -naphthyl.
  • Exemplary fluoxetine structural analogs are 3-(p-isopropoxyphenoxy)-3- phenylpropylamine methanesulfonate, N,N-dimethyl 3-(3',4'- dimethoxyphenoxy)-3 -phenylpropy lamine p-hy droxybenzoate, N,N-dimethy 1 3-( ⁇ -naphthoxy)-3-phenylpropylamine bromide, N,N-dimethyl 3-( ⁇ - naphthoxy)-3-phenyl-l-methylpropy lamine iodide, 3-(2'-methyl-4',5 l - dichlorophenoxy)-3 -phenylpropy lamine nitrate, 3-(p-t-butylphenoxy)-3- phenylpropylamine glutarate, N-methyl 3-(2'-chloro-p-tolyloxy)-3-phenyl-l- methylpropylamine lactate, 3-(2',4
  • Fluvoxamine has the following structure:
  • Structural analogs of fluvoxamine are described by Formula (I) in U.S. Patent No. 4,085,225. Structural analogs of fluvoxamine are also described by the formula:
  • R is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl.
  • Indalpine has the following structure:
  • Structural analogs of indalpine are those having the formula:
  • R 1 is a hydrogen atom, a CpC 6 alkyl group, or an aralkyl group of which the alkyl has 1 or 2 carbon atoms
  • R 2 is hydrogen, Q-C 6 alkyl, CpC 6 alkoxy or CpC 6 alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy, or amino, the latter optionally substituted by one or two Cj-C 6 alkyl groups, an acyl group or a C 1 -C 6 alkylsulfonyl group
  • A represents -CO or -CH 2 - group
  • n is 0, 1 or 2.
  • indalpine structural analogs are indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4 methyl) ketone; (chloro-5- indolyl-3) (piperidyl-4 methyl) ketone; (indolyl-3 )-l(piperidyl-4)-3 propanone, indolyl-3 piperidyl-4 ketone; (methyl- 1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl- 1 indolyl-3) (piperidyl-4 methyl) ketone; [(methoxy-5 indolyl-3)-2 ethyl]-piperidine, [(methyl- 1 indolyl-3)-2 ethyl] -4-piperi dine; [(indolyl-3 )-2 ethyl]-4 piperidine; (indolyl-3 methyl)
  • Indeloxezine has the following structure:
  • Structural analogs of indeloxazine are those having the formula:
  • R 1 and R 3 each represents hydrogen, C 1 -C ⁇ alkyl, or phenyl
  • R 2 represents hydrogen, C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, phenyl, or benzyl
  • one of the dotted lines means a single bond and the other means a double bond, or the tautomeric mixtures thereof.
  • Exemplary indeloxazine structural analogs are 2-(7-indenyloxymethyl)- 4-isopropylmo ⁇ holine; 4-butyl-2-(7-indenyloxymethyl)morpholine; 2-(7- indenyloxymethyl)-4-methylmorpholine; 4-ethyl-2-(7- indenyloxymethyl)mo ⁇ holine, 2-(7-indenyloxymethyl)-morpholine; 2-(7- indenyloxymethyl)-4-propylmo ⁇ holine; 4-cyclohexyl-2-(7- indenyloxymethyl)mo ⁇ holine; 4-benzyl-2-(7-indenyloxymethyl)-mo ⁇ holine; 2-(7-indenyloxymethyl)-4-phenylmo ⁇ holine; 2-(4- indenyloxymethyl)mo ⁇ holine; 2-(3-methyl-7-indenyloxymethyl)-mo ⁇ holine; 4-isopropyl-2-(3-
  • Milnacipram has the following structure:
  • each R independently, represents hydrogen, bromo, chloro, fluoro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, nitro or amino
  • each of Rj and R 2 independently, represents hydrogen, Q-C 6 alkyl, C 6 -Ci 2 ar yl or C 7 -C 14 alkylaryl, optionally substituted, for example, in para position, by bromo, chloro, or fluoro, or Rj and R 2 together form a heterocycle having 5 or 6 members with the adjacent nitrogen atoms
  • R 3 and R 4 represent hydrogen or a CpC 6 alkyl group or R 3 and R 4 form with the adjacent nitrogen atom a heterocycle having 5 or 6 members, optionally containing an additional heteroatom selected from nitrogen, sulphur, and oxygen.
  • Exemplary milnacipram structural analogs are 1 -phenyl 1- aminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- diethylaminocarbonyl 2-aminomethyl cyclopropane; 1 -phenyl 2- dimethylaminomethyl N-(4'-chlorophenyl)cyclopropane carboxamide; 1- phenyl 2-dimethylaminomethyl N-(4'-chlorobenzyl)cyclopropane carboxamide; 1 -phenyl 2-dimethylaminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3,4-dichloro-l -phenyl) 2-dimethylamino
  • Paroxetine Paroxetine has the following structure:
  • Structural analogs of paroxetine are those having the formula:
  • Rj represents hydrogen, optionally substituted Ci -6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl
  • R 2 is optionally substituted Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2 -C 6 -heterocyclyl or C 6 -Ci 2 aryl
  • X is any halogen and may be in any of the available positions
  • Y is O or S.
  • Paroxetine analogs may be used as stereochemical mixtures or in stereochemically pure form.
  • An exemplary value for R 2 is optionally substituted 1,3-benzodioxole.
  • Sertraline has the following structure:
  • Structural analogs of sertraline are those having the formula: wherein, independently, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen or optionally substituted C 1 -G 6 alkyl; X and Y are each selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, C 1 -C 3 alkoxy, and cyano; and W is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and C 1 -C 3 alkoxy.
  • the sertraline analogs are in the cis-isomeric configuration.
  • cis-isomeric refers to the relative orientation of the NRiR 2 and phenyl moieties on the cyclohexene ring (i.e. they are both oriented on the same side of the ring). Because both the 1- and 4- carbons are asymmetrically substituted, each cis- compound has two optically active enantiomeric forms denoted (with reference to the 1 -carbon) as the cis-(lR) and cis-(l S) enantiomers.
  • Sertraline analogs are also described in U.S. Pat. No. 4,536,518.
  • Other related compounds include (S,S)-N-desmethylsertraline, rac-cis-N- desmethylsertraline, (lS,4S)-desmethyl sertraline, 1-des (methylamine)-l-oxo- 2-(R,S)-hydroxy sertraline, (lR,4R)-desmethyl sertraline, sertraline sulfonamide, sertraline (reverse) methanesulfonamide, 1R,4R sertraline enantiomer, N,N-dimethyl sertraline, nitro sertraline, sertraline aniline, sertraline iodide, sertraline sulfonamide NH 2 , sertraline sulfonamide ethanol, sertraline nitrile, sertraline-CME, dimethyl sertraline reverse sulfonamide, sertraline reverse sulfonamide (CH 2 linker
  • Zimeldine has the following structure:
  • Structural analogs of zimeldine are those compounds having the formula:
  • pyridine nucleus is bound in ortho-, meta- or para-position to the adjacent carbon atom and where R 1 is selected from the group consisting of H, chloro, fluoro, and bromo.
  • Exemplary zimeldine analogs are (e)- and (z)- 3-(4'-bromophenyl-3-(2"- pyridyl)-dimethylallylamine; 3-(4'-bromophenyl)-3-(3 "-pyridyl)- dimethylallylamine; 3-(4'-bromophenyl)-3-(4"-pyridyl)-dimethylallylamine; and pharmaceutically acceptable salts of any thereof.
  • Structural analogs of any of the above SSRIs are considered herein to be SSRI analogs and thus may be employed in any of the methods, compositions, and kits described herein.
  • Pharmacologically active metabolites of any of the foregoing SSRIs can also be used in the methods, compositions, and kits described herein.
  • Exemplary metabolites are didesmethylcitalopram, desmethylcitalopram, desmethylsertraline, and norfluoxetine.
  • SSRIs serotonin norepinephrine reuptake inhibitors
  • SNRIs selective serotonin norepinephrine reuptake inhibitors
  • Venlafaxine Venlafaxine has the following structure:
  • Structural analogs of venlafaxine are those compounds having the formula:
  • R 1 is hydrogen or alkyl
  • R 2 is C]-C 6 alkyl
  • R 4 is hydrogen, CpC 6 alkyl, formyl or alkanoyl
  • R 3 is hydrogen or CpC 6 alkyl
  • R 5 and R 6 are, independently, hydrogen, hydroxyl, C r C 6 alkyl, CpC 6 alkoxy, CpC 6 alkanoyloxy, cyano, nitro, alkylmercapto, amino, C 1 -C 6 alkylamino, dialkylamino, CpC 6 alkanamido, halo, trifluoromethyl or, taken together, methylenedioxy
  • n is 0, 1, 2, 3 or 4.
  • Duloxetine has the following structure:
  • Structural analogs of duloxetine are those compounds described by the formula disclosed in U.S. Patent No. 4,956,388 and in U.S. Patent No. 5,023,269 (see, for example, the formula at Col. 1, line 35 and the formula recited in Claim 1).
  • duloxetine analogs are: N-Methyl-3-(l-naphthalenyloxy)-3-(3- thienyl)-propanamine; N-Methyl-3-(2-naphthalenyloxy)-3-(cyclohexyl)- propanamine; N,N-Dimethyl-3-(4-chloro- 1 -naphthalenyloxy)-3-(3- furanyl)propanamine; N-Methyl-3-(5-methyl-2-naphthalenyloxy)-3-(2- thiazolyl)propanamine; N-Methyl-3-[3-(trifluoromethyl)- 1 -naphthalemyloxy]- 3-(3-methyl-2-thienyl)propanamine; N-Methyl-3-(6-iodo-l-naphthalenyloxy)- 3-(4-pyridyl)propanamine; N,N-Dimethyl-3-(l-n-
  • SSRJ analogs are l,2,3,4-tetrahydro-N-methyl-4-phenyl-l- naphthy lamine hydrochloride; 1 ,2,3 ,4-tetrahydro-N-methyl-4-pheny 1-(E)- 1 - naphthylamine hydrochloride; N,N-dimethyl- 1 -phenyl- 1 -phthalanpropylamine hydrochloride; gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine hydrochloride; BP 554; CP 53261; O-desmethylvenlafaxine; WY 45,818; WY 45,881; N-(3-fluoropropyl)paroxetine; and Lu 19005.
  • Anticholinergic agents are compounds that reduce the effects mediated by acetylcholine at a receptor site, e.g., in the central nervous system or peripheral nervous system.
  • Anticholinergics include reversible competitive inhibitors of acetylcholine receptors, and are classified according to the receptors that are affected: antimuscarinic agents operate on the muscarinic acetylcholine receptors, and antinicotinic agents operate on the nicotinic acetylcholine receptors.
  • Anticholinergic agents may be used to treat neurodegenerative disorders.
  • Anticholinergic agents that may be suitable for use in the compositions, kits, and methods described herein include, e.g., atracurium; atropine; benztropine (e.g., benztropine mesylate); darifenacin; dicyclomine (e.g., dicyclomine hydrochloride); dimenhydrinate; diphenhydramine; doxacurium; ethopropazine (e.g., ethopropazine hydrochloride); flavoxate; ipratropium; mivacurium; oxybutynin; pancuronium; pirenzepine; scopolamine; solifenacin; suxamethonium (e.g., suxamethonium chloride); tiotropium; tolterodine (e.g., tolterodine tartrate); trihexyphenidyl (e.g., trihexyphenidyl hydrochloride); trime
  • Benztropine has the following structure:
  • Ethopropazine has the structure
  • each Xj and X 2 is selected from H, halogen, OH, CN, NO 2 , C 1-6 alkyl, or OCi -6 alkyl; n is 0, 1, 2, 3, 4, 5, or 6; and R 1 , R 2 , and R 3 are H or optionally substituted Ci -6 alkyl, or R 2 , and R 3 join to form a ring.
  • Trihexyphenidyl hydrochloride has the following structure:
  • Structural analogs of trihexyphenidyl are described by Formulas (I) and (II) in U.S. Patent No. 2,682,543 and by the general formula found in U.S. Patent No. 2,716,121. Structural analogs of trihexyphenidyl can also have the following structure
  • Ri, R 2 , R 3 , R 4 , and R 5 are H, halogen, OH, CN, NO 2 , C 1-6 alkyl, or OCi -6 alkyl; Ai and A 2 are H or optionally substituted Ci -6 alkyl, or A 1 and A 2 join together to form a ring; n is 1, 2, 3, 4, 5, or 6; and B 1 and B 2 are H or optionally substituted C 1-6 alkyl, or B] and B 2 join together to form a ring.
  • Estrogen modulators may be useful in the compositions, methods, and kits described herein.
  • Estrogen modulators include selective and non-selective estrogen receptor modulators, and further include estrogen-like compounds that modulate estrogen levels.
  • Estrogen modulators include estrogenic antagonists, e.g., antiestrogens, and estrogenic agonists.
  • Selective estrogen receptor modulators are high affinity ligands for estrogen receptors but can serve as either agonists or antagonists, depending on the tissue in which they act.
  • Exemplary estrogen modulators are acolbifene, afimoxifene, arzoxifene, clomifene (or clomiphene), N-desmethyltamoxifen, desmethylated arzoxifene, droloxifene, faslodex, 4'-fluoro- desmethylatedarzoxifene, fispemifene, fiilvestrant, 4-hydroxy tamoxifen, idoxifene, lasofoxifene, levormeloxifene, miproxifene, nafoxidine, ormeloxifene, ospemifene, pipendoxifene, raloxifene, tamoxifen, toremifene, trioxifene, CI-680, CI-628, CN-55,956-27, MER-25, U-11,555A, U-I l 5 IOOA, ICI-46
  • Clomiphene Clomiphene has the following structure:
  • Structural analogs of clomiphene include the other olefinic diastereomer of clomiphene. Structural analogs are also described by the general formula in U.S. Patent No. 2,914,563; the general formula of U.S. Patent No. 5,410,080; and in U.S. Patent No. 5,189,212.
  • Raloxifene has the following structure:
  • Exemplary structural analogs of raloxifene are LYl 17018 and LY317783. Analogs of raloxifene are also described by Formula (I) of U.S. Patent No. 5,610,167 and also in U.S. Patent Nos. 5,393,763; 5,457,117; 5,478,847; 5,811,120; 5,972,383; 6,458,811 ; 6,797,719; 6,894,064; 6,906,086; RE38,968; RE39,049; RE39,050; and RE39,708; and in WO2000037065.
  • Tamoxifen has the following structure:
  • Structural analogs of tamoxifen have the following structure:
  • Exemplary analogs of tamoxifen also include: 4-hydroxy tamoxifen; N- desmethyltamoxifen; threo- l-[4-(2,3-epoxypropoxy)-phenyl]- 1 ,2-diphenyl- 3,3,3-trifluoro-propane; (E)l-[4-(2,3-epoxypropoxy)-phenyl]-l,2-diphenyl- 3,3,3-trifluoro-propene; (E)-l,2-diphenyl-3,3,3-trifluoro-l-[4-(2-[bis-(2- hydroxyethyl)-amino]-eth oxy)-phenyl)]-propene: (E)-l,2-diphenyl-3,3,3- trifluoro- 1 -[4-(2-[4-methylpiperazino]-ethoxy)-phenyl]-propene; 1 -[4-(2- dimethy
  • Toremifene has the following structure:
  • IKK- ⁇ inhibitors are described by: Formulas (I), (II), (III), and (IV) in U.S. Patent Nos. 5,939,421 and 6,150,372; Formulas (I) and (II) in U.S. Patent Nos. 6,627,637 and 7,026,331; Formulas (I) and (If) and Compound 6 in WO2002060386 and U.S. Patent No. 6,869,956; Formula (I) and (If) in U.S.
  • IKK- ⁇ inhibitors include but are not limited to: MLN0415 ;
  • IMD-0354 is an IKK- ⁇ inhibitor and has the following structure:
  • Analogs of IMD-0354 include other small molecule NF- ⁇ B inhibitors.
  • Exemplary small molecule NF- ⁇ B inhibitors are: antioxidants; SP 100030; dehydroxymethylepoxyquinomicin (DHMEQ); Formula (I) in WO2006/032322, hereby incorporated by reference.
  • Analogs of IMD-0354 are also described by the following formula
  • X is halogen at any position of the ring; X is O or X; R 1 , R 2 , R 3 , R 4 , and R 5 are H or perhalogenated C 1-6 alkyl; and R 6 is H or Ci -6 alkyl.
  • Alverine has the following structure:
  • R 1 is H or C 1-6 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Rj 0 , and R n are selected from H, halogen, OH, C 1-6 alkyl, and OC 1-6 alkyl
  • m is 0, 1, 2, 3, 4, 5, or 6
  • n is 0, 1, 2, 3, 4, 5 or6.
  • Amiodarone has the following structure:
  • Structural analogs of amiodarone are described by the general formula and Examples I, II, and III found in U.S. Patent No. 3,248,401; the general formula in U.S. Patent No. 5,849,788 (see, for example, claim 1); the compounds disclosed in U.S. Patent No. 5,567,728; and Formula (I) in U.S. Patent No. 4,851,554. Additional analogs of amiodarone are found in U.S. Patent Nos. 7,148,240; 6,515,147; 6,316,487; and 5,981,514.
  • Exemplary structural analogs of amiodarone are: 3,5-diiodo-4-(2-N,N- diethylaminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride; 2- methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino-ethoxy)-benzoyl)benzofuran hydrochloride; 2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy- benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran; 4'-hydroxy-3'- iodo-3,5 diiodo-4-(2-N,N-dimethylamino-ethoxy)benzophenone hydroch
  • Chloroquine has the following structure:
  • Hydroxychloroquine has the following structure:
  • Ri, R 2 , R 3 , R 4 , and R 5 are selected from H, halogen, Ci -6 alkyl, OH, OCi -6 alkyl, CN, or NO 2 ;
  • A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive;
  • R 6 , R 7 , Rg, and R 9 are H, Ci -6 alkyl, or (CH 2 ) n (CH 2 OH) where n is 0, 1, 2, 3, 4, or 5.
  • Chlorprothixene has the following structure:
  • Structural analogs of chlorprothixene have the following structure: wherein, independently, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rs, and R 9 , are each selected from H, halogen, C 1-6 alkyl, perhalogenated Ci -6 alkyl, OH, OC 1-6 alkyl, OCF 3 , SH, SCi -6 alkyl, or SCF 3 , wherein at least one OfR 1 -R 8 is a halogen; Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; Bi and B 2 are selected from H, perhalogenated C 1-6 alkyl, C 1-6 alkyl, or Bi and B 2 join
  • Dicyclomine has the following structure:
  • Structural analogs of dicyclomine are described in U.S. Patent No. 2,474,796. Structural analogs of dicyclomine are also described by the following formula
  • n 1, 2, 3, 4, 5 ,or 6
  • X and Y are selected from O and S
  • Ri and R 2 are H or Ci -6 alkyl.
  • Hexachlorophene has the following structure:
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are H or halogen and n is O, 1, 2, 3, 4, or 5.
  • Nitazoxanide has the following structure:
  • Structural analogs of nitazoxanide include tizoxanide or have the following structure:
  • R 1 and R 2 are selected from H, halogen, CN, NO 2 , CF 3 , or Ci -6 alkyl;
  • R 3 is H or Ci -6 alkyl;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are selected from H, halogen, CN, NO 2 , CF 3 , Ci -6 alkyl, or OCj -6 alkyl;
  • X, Y, and Z is selected from O, S, or NR 9 ;
  • A is a bond, O, S, or NR 9 ;
  • R 9 is H or Ci -6 alkyl; and
  • B is H or C(Z)-X-R 8 .
  • Thioridazine has the following structure:
  • Structural analogs of thioridazine have the structure wherein, independently, Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and Rg are each selected from H, halogen, C 1-6 alkyl, perhalogenated Ci -6 alkyl, OH, OCi -6 alkyl, OCF 3 , SH, SC, -6 alkyl, or SCF 3 ; Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S; A is a bond or a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; each Bi, B 2 , B 3 , and B 4 is, independently, H, halogen, perhalogenated Ci -6 alkyl, Ci -6 alkyl, OCi -6 alkyl, O(per
  • Thioridazine analogs are also described by Formulas (I), (IIA), and (IIB) in U.S. Application Publication No. 2007-0287702.
  • Vanoxerine has the structure:
  • therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents.
  • Agents that may be particularly useful include those that prevent or slow the rate of neural deterioration or death, or those that treat, prevent, or ameliorate one or more symptoms of a neurodegenerative disorder.
  • Exemplary therapeutic classes and agents are listed in Table 2. Combinations of the classes and agents of Table 2 may also be used. If more than one agent is employed, therapeutic agents may be delivered separately or may be admixed into a single formulation. When agents are present in different pharmaceutical compositions, different routes of administration may be employed.
  • Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration).
  • agents may be administered by intracranial, intrathecal, or epidural administration. Any method of administration that bypasses the blood-brain barrier or enhances its permeability (e.g., administration of a NaVCa + * exchange blocker, mannitol, or Cereport) may be useful.
  • an agent and additional therapeutic agents are administered at least one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently. For example, one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions described herein to a patient.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds, described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve other therapies, e.g., transplantation of neural cells (including, if needed, anti-inflammatory and/or immunosuppressive therapy), or a modification to the lifestyle of the patient being treated.
  • therapies e.g., transplantation of neural cells (including, if needed, anti-inflammatory and/or immunosuppressive therapy), or a modification to the lifestyle of the patient being treated.
  • the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula I.
  • (A) is an agent listed in Table Ia or Ib covalently tethered via a linker (L) to (B), any agent of the classes and agents listed in Tables Ia, Ib, and 2.
  • Conjugates can be administered to a subject by any route and for the treatment of any disease described herein.
  • the conjugates can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases).
  • the conjugates can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
  • Conjugates can be prepared using techniques familiar to those skilled in the art.
  • the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996.
  • the synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B).
  • commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl.
  • amides such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides.
  • protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters.
  • Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers.
  • Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls.
  • sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides).
  • Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule.
  • the conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and PJ. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
  • the linker component is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
  • linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B).
  • functional groups located on drug (A) and drug (B).
  • chemically reactive functional groups include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
  • the covalent linking of drug (A) and drug (B) may be effected using a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an amide linking the two.
  • N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions.
  • Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
  • reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents.
  • Representative alkylating agents include:
  • N-maleimide derivatives which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91 :589 (1964);
  • aryl halides such as reactive nitrohaloaromatic compounds;
  • epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups;
  • Representative amino-reactive acylating agents include: (i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively;
  • acylazides e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974); and (viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962).
  • Aldehydes and ketones may be reacted with amines to form Schiff s bases, which may advantageously be stabilized through reductive amination.
  • Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1 :96 (1990).
  • reactive moieties capable of reaction with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947).
  • Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed. It will be appreciated that functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity.
  • Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as ⁇ -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
  • So-called zero-length linkers involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used.
  • the linker will include two or more reactive moieties, as described above, connected by a spacer element.
  • the presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two.
  • the reactive moieties in a linker may be the same (homobifunctional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
  • Spacer elements in the linker typically consist of linear or branched chains and may include a C 1 -Ci 0 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C] 2 aryl, C 7 -C 14 alkaryl, C 3 -Ci 0 alkheterocyclyl, or C 1 -C 10 heteroalkyl.
  • the linker is described by formula (II):
  • G 1 is a bond between drug (A) and the linker;
  • G 2 is a bond between the linker and drug (B);
  • Z 1 , Z 2 , Z 3 , and Z 4 each, independently, is selected from O, S, and NR 31 ;
  • R 31 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C 12 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, or C 1 -C 7 heteroalkyl;
  • R 30 is a C 1 -C 10 alkyl, C 2
  • homobifunctional linkers useful in the preparation of conjugates include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.
  • diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.
  • any of the agents described herein may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents. Such co-formulated compositions can include the two agents formulated together in the same pill, capsule, liquid, etc. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations described herein. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging").
  • the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
  • BBB blood-brain barrier
  • Craniotomy a procedure known in the art, can be used with any composition described herein for delivery to the brain.
  • an opening is made in the patient's cranium, and a compound is delivered via a catheter.
  • This approach can be used to target a compound to a specific area of the brain.
  • Intrathecal administration provides another means of bypassing the BBB for drug delivery.
  • drugs are administered to the spinal chord, for example, via lumbar puncture or through the use of devices such as pumps.
  • Lumbar puncture may be used for single or infrequent administration, whereas constant and/or chronic administration may be achieved using any commercially available pump attached to a intraspinal catheter, e.g., a pump and catheter made by Medtronic (Minneapolis, Minn.).
  • a pump and catheter made by Medtronic (Minneapolis, Minn.).
  • compositions described herein can be administered along with a compound or compounds that induce a transient increase in permeability of the BBB.
  • Such compounds include mannitol, Cereport (RMP-7), and KB-R7943, a Na + ZCa 4"1" exchange blocker.
  • Compounds described herein can be modified (e.g., lipidated or acetylated) to increase transport across the BBB following systemic administration (e.g., parenteral) by using chemical modifications that are standard in the art.
  • compounds described herein are conjugated to peptide vectors that are transported across the BBB.
  • compounds may be conjugated to a monoclonal antibody to the human insulin receptor as described by Partridge (Jpn. J. Pharmacol. 87:97- 103, 2001), thus permitting the compound to be transported across the BBB following systemic administration.
  • Compounds described herein can be conjugated to such peptide vectors, for example, using biotin-streptavidin technology.
  • the dosage of any of the agents of the combinations described herein will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2,000 mg per day, about 1 mg to 1,000 mg per day, or about 5 mg to 500 mg per day.
  • Administration of each drug in the combination can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Additional Applications
  • compounds may be employed in mechanistic assays to determine whether other combinations, or single agents, are as effective as the combination in treating, preventing, or ameliorating neurodegenerative disorders (e.g., HD or any of its associated conditions) using assays generally known in the art, examples of which are described herein.
  • candidate compounds may be tested, alone or in combination with one or more compounds selected independently from any of the agents of Tables Ia and Ib, and applied to cells, e.g., neural cells or mouse striatal knock-in cell line STHdhQ 111 expressing a toxic mutant polyglutamine repeat protein. After a suitable time, these cells are examined for immunoreactivity using the polyQ antibody, 1F8. A decrease in perinuclear staining, in comparison to control cells not treated with the candidate compound, identifies a candidate compound or combination of agents as an effective agent to treat, prevent, or ameliorate a neurodegenerative disorder.
  • the agents described herein may also be useful tools in elucidating mechanistic information about the biological pathways involved in neural cell deterioration and death. Such information can lead to the development of new combinations or single agents for treating, preventing, or ameliorating neurodegenerative disorders.
  • Methods known in the art to determine biological pathways can be used to determine the pathway, or network of pathways, affected by contacting cells, e.g., neural cells, with the compounds described herein. Such methods can include analyzing cellular constituents that are expressed or repressed after contact with the compounds described herein as compared to untreated, positive or negative control compounds, and/or new single agents and combinations, or analyzing some other activity of the cell such as enzyme activity, nutrient uptake, and proliferation.
  • Cellular components analyzed can include gene transcripts and protein expression.
  • Suitable methods can include standard biochemistry techniques, radiolabeling the compounds described herein (e.g., 14 C or ⁇ labeling), and observing the compounds binding to proteins, e.g. using 2D gels, gene expression profiling. Once identified, such compounds can be used in in vivo models to further validate the tool or develop new agents or strategies to treat, prevent, or ameliorate neurodegenerative disorders.
  • the methods described herein may also be used prophylactically, in patients who are at an increased risk of developing a neurodegenerative disorder, e.g., HD, or a condition associated with such a disorder.
  • a neurodegenerative disorder e.g., HD
  • Risk factors include, for example, age, family history of neurodegenerative disorders, and psychological or psychiatric profile.
  • Peptides, peptide mimetics, and peptide fragments may be suitable for use.
  • exemplary compounds include those that reduce the amount of target protein or RNA levels (e.g., antisense compounds, dsRNA, ribozymes) and compounds that compete with endogenous mitotic kinesins or protein tyrosine phosphatases for binding partners (e.g., dominant negative proteins or polynucleotides encoding the same).
  • RNA secondary structure folding program such as MFOLD (M. Zuker, D. H. Mathews & D. H. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic Publishers, (1999)).
  • Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond. Open regions that do not form a base pair are summed together with each suboptimal fold and areas that are predicted as open are considered more accessible to the binding to antisense nucleobase oligomers.
  • Other methods for antisense design are described, for example, in U.S. Patent No. 6,472,521, Antisense Nucleic Acid Drug Dev. 1997 7:439-444, Nucleic Acids Research 28:2597-2604, 2000, and Nucleic Acids Research 31 :4989-4994, 2003.
  • RNA Interference The biological activity of a target molecule can be reduced through the use of RNA interference (RNAi), employing, e.g., a double stranded RNA (dsRNA) or small interfering RNA (siRNA) directed to the target molecule in question (see, e.g., Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003; U.S. Patent Application Publication No. 20030157030).
  • dsRNA double stranded RNA
  • siRNA small interfering RNA
  • Methods for designing such interfering RNAs are known in the art. For example, software for designing interfering RNA is available from Oligoengine (Seattle, WA).
  • Example 1 Screening Assays Provided are screening methods for identifying candidate compounds that treat, prevent, or ameliorate neurodegenerative disorders, e.g., HD.
  • Htt a variety of model systems, including cellular as well as animal models, have demonstrated that the exon 1 portion of Htt, containing an expanded polyglutamine region, is sufficient to cause pathology.
  • STHdhQl 11 cell line derived from the HD knock-in mouse model which expresses mutant Htt at endogenous level with the right genetic context, has been widely used and well characterized. This cell line recapitulates many HD pathogenic features, such as mitochdria dysfunction and energy deficiency, and thus is regarded as one of the most HD-relevant cellular models.
  • HCS high content screening
  • % of inhibition [(DMSO treated-compound treated)/DMSO treated] 100 More than 50% of killing was consistently achieved 72 hours following hexachlorophene treatment when comparing with DMSO-treated wells.
  • Single agent curve data were used to define a dilution series for each compound to be used for combination screening in a 6x6 matrix format.
  • a dilution factor f of 2, 3, or 4, depending on the sigmoidicity of the single agent curve, five dose levels were chosen with the central concentration close to the fitted EC 50 .
  • a dilution factor of 4 was used, starting from the highest achievable concentration.
  • Combination effects can be most readily characterized by comparing each data point's inhibition to that of a combination reference model that was derived from the single agent curves.
  • HSA highest single agent
  • Loewe additivity is a generally accepted reference for synergy, as it represents the combination response generated if X and Y are the same compound. / HSA is easily calculated from / X)Y , but determining / Loewe requires interpolation and numerical root finding.
  • the automated analysis first determined plates to be verified, rejected or undetermined. All plates were then evaluated manually on a plate-by-plate basis and, if necessary, assigned a status of hand accepted or rejected. Additionally, individual blocks of data on verified plates could be manually marked for exclusion.
  • the quality control criterion for automated analysis was called the Z'- factor, which is defined as:
  • SD represents standard deviation
  • DMSO represents vehicle treated
  • Control represents the background which is defined by wells undergoing all the assay procedures but without the secondary antibody.
  • any cell line expressing a CAG repeat gene containing an expanded CAG repeat region may be used.
  • Screening assays directed to a given polyglutamine repeat disorder may be varied, e.g., by utilizing a cell line expressing a polyglutamine repeat protein, or fragment thereof, associated with that disorder. Any cutoff for hit picking may be chosen, e.g., 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • any method of assaying cell viability may be employed.
  • Example 2 Further Screening Assay: Protocol for TMRE Assay Using Mouse Striatal Cell Lines
  • the protocol for the screening method is provided below.
  • FCCP FCCP stock: 50 ⁇ M in DMSO

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions, des kits et des procédés de traitement, de prévention et d'amélioration de maladies neurodégénératives, par exemple la maladie de Huntington.
PCT/US2008/005194 2007-04-23 2008-04-23 Procédés et compositions pour traiter des maladies neurodégénératives WO2008133884A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US92575307P 2007-04-23 2007-04-23
US60/925,753 2007-04-23
US95877407P 2007-07-09 2007-07-09
US60/958,774 2007-07-09

Publications (1)

Publication Number Publication Date
WO2008133884A2 true WO2008133884A2 (fr) 2008-11-06

Family

ID=39926265

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/005194 WO2008133884A2 (fr) 2007-04-23 2008-04-23 Procédés et compositions pour traiter des maladies neurodégénératives

Country Status (2)

Country Link
TW (1) TW200848063A (fr)
WO (1) WO2008133884A2 (fr)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009087351A1 (fr) * 2008-01-04 2009-07-16 Gw Pharma Limited Utilisation de cannabinoïdes en combinaison avec un médicament antipsychotique
WO2010013127A1 (fr) * 2008-07-31 2010-02-04 Servicios Cientificos Neuroinnovation Ltda. Composés dérivés de benzimidazoles utiles en tant que marqueurs pour les maladies neurodégénératives
US20100234402A1 (en) * 2007-05-31 2010-09-16 Gideon Dreyfuss Methods and compositions for treating spinal muscular atrophy
WO2010132810A1 (fr) * 2009-05-15 2010-11-18 Concert Pharmaceuticals, Inc. Benzimidazoles
EP2266550A1 (fr) * 2009-06-15 2010-12-29 Institut Curie Antagonistes de bêta-caténine pour la prévention et/ou le traitement des troubles neuro-dégénératifs
WO2011060962A1 (fr) * 2009-11-23 2011-05-26 Laboratorios Del Dr. Esteve, S.A. Sels de duloxétine et nsaid pour le traitement de la douleur
EP2327703A1 (fr) * 2008-08-22 2011-06-01 IVASHCHENKO, Andrey Alexandrovich Ligand possédant une gamme étendue d activité pharmacologique, composition pharmaceutique, médicament et méthode de traitement
WO2011041731A3 (fr) * 2009-10-02 2011-06-16 Fred Hutchinson Cancer Research Center Procédé destiné à inhiber des protéines de survie apparentées aux bcl-2
US20110195049A1 (en) * 2008-10-13 2011-08-11 Biovista, Inc. Compositions and methods for treating multiple sclerosis
WO2011107583A1 (fr) * 2010-03-04 2011-09-09 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 4-phényle-n-alkyle-pipéridines substituées destinées à prévenir le début ou à ralentir la progression de maladies neurodégénératives
DE102010062810A1 (de) * 2010-09-07 2012-03-08 Universität Rostock 2-(R2-Thio)-10-[3-(4-R1-piperazin-1-yl)propyl]-10H-phenothiazine zur Behandlung neurodegenerativer Erkrankungen
CN103070876A (zh) * 2011-10-25 2013-05-01 中国农业科学院上海兽医研究所 一类抗乙型脑炎病毒感染的组合物及其应用
US20130225642A1 (en) * 2010-09-02 2013-08-29 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
WO2013152105A1 (fr) 2012-04-04 2013-10-10 IVAX International GmbH Compositions pharmaceutiques pour traitement combiné
WO2013179144A3 (fr) * 2012-06-01 2014-03-13 Oxalys Pharmaceuticals Suppresseurs chimiques de la neurotoxicité dans les maladies synucléinopathiques
US8865901B2 (en) 2009-10-02 2014-10-21 Fred Hutchinson Cancer Research Center Gain-of-function Bcl-2 inhibitors
WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication
US9114130B2 (en) 2013-05-06 2015-08-25 University Of South Florida Compounds and related methods for treatment of neurodegenerative diseases
CN105078947A (zh) * 2015-08-07 2015-11-25 王红兵 他莫昔芬的用途
US20160008320A1 (en) * 2014-07-14 2016-01-14 University Of Washington Statins in the treatment of muscular dystrophies and myopathies
EP3034074A1 (fr) 2014-12-18 2016-06-22 Universitat De València, Estudi General Composé pour le traitement de la dystrophie myotonique de type 1
US9381249B2 (en) 2012-06-05 2016-07-05 Neuroderm, Ltd. Compositions comprising apomorphine and organic acids and uses thereof
WO2016138138A1 (fr) * 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles
CN105920019A (zh) * 2016-07-05 2016-09-07 福州大学 一种含熊果酸与索拉菲尼的药物组合物及其在制备抗肿瘤药物中的应用
CN105924641A (zh) * 2016-06-06 2016-09-07 陕西省科学院酶工程研究院 一种硫酸羟基氯喹聚谷氨酸聚合物及其制备方法和应用
CN107375280A (zh) * 2016-05-17 2017-11-24 中国科学院上海药物研究所 硝唑尼特及其药学上可接受的盐在制备用于治疗阿尔茨海默病的药物中的应用
WO2018136600A1 (fr) 2017-01-20 2018-07-26 Teva Pharmaceuticals International Gmbh Utilisation de pridopidine pour traiter le syndrome de l'x fragile
US10064850B2 (en) 2007-04-11 2018-09-04 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
WO2018176098A1 (fr) 2017-03-31 2018-10-04 The Florey Institute Of Neuroscience And Mental Health Prophylaxie et traitement d'un dysfonctionnement et d'un déclin cognitifs
US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases
CN109414418A (zh) * 2016-06-29 2019-03-01 瓦伦塔有限责任公司 包含美金刚和褪黑素的组合的药物组合物
WO2019241376A1 (fr) * 2018-06-14 2019-12-19 The Trustees Of Columbia University In The City Of New York Traitement de troubles cognitifs à l'aide de nitazoxanide (ntz), d'analogues de nitazoxanide (ntz) et de leurs métabolites
US10751353B2 (en) * 2013-05-07 2020-08-25 Seelos Therapeutics, Inc. Compositions and methods for treating an aggregation disease or disorder
US10780149B2 (en) * 2015-04-24 2020-09-22 Consiglio Nazionale Delle Ricerche Therapeutic use of the botulinum neurotoxin serotype A
US10869831B2 (en) 2013-05-07 2020-12-22 Seelos Therapeutics, Inc. Treatment of protein aggregation myopathic and neurodegenerative diseases by parenteral administration of trehalose
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
EP3634410A4 (fr) * 2017-06-05 2021-03-03 The Methodist Hospital System Inhibiteurs de phosphorylation des protéines tau et méthodes de traitement ou de prévention de la maladie d'alzheimer
US10973890B2 (en) 2016-09-13 2021-04-13 Allergan, Inc. Non-protein clostridial toxin compositions
CN112641784A (zh) * 2020-12-31 2021-04-13 南京中医药大学 一种具有治疗神经元损伤及/或神经炎症相关的神经退行性疾病作用的药物组合物
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
WO2021161319A1 (fr) * 2020-02-13 2021-08-19 Prilenia Neurotherapeutics Ltd. Polythérapie pour le traitement de la sclérose latérale amyotrophique à l'aide de pridopidine et d'un autre agent actif
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
CN114470215A (zh) * 2020-11-12 2022-05-13 北京科辉智药生物科技有限责任公司 Sarm1酶活性抑制剂及其在神经退行性疾病中的应用
US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy
US11406625B2 (en) 2017-08-14 2022-08-09 Prilenia Neurotherapeutics Ltd. Method of treating amyotrophic lateral sclerosis with pridopidine
EP4134363A1 (fr) * 2020-04-09 2023-02-15 Aventi Inc. Composition pharmaceutique pour la prévention ou le traitement de maladies associées à une faiblesse musculaire comprenant l'alvérine, 4-hydroxy alvérine ou un dérivé correspondant ou leur sel pharmaceutiquement acceptable
WO2023019823A1 (fr) * 2021-08-17 2023-02-23 南京中医药大学 Utilisation de desloratadine et de sel correspondant dans la préparation d'un médicament destiné au traitement de maladies neurodégénératives liées à un dysfonctionnement moteur
US11590093B2 (en) * 2018-04-13 2023-02-28 Healx Limited Kit, composition, and combination therapy for fragile X syndrome
US20230233595A1 (en) * 2022-01-25 2023-07-27 New York Medical College Use of stat4 inhibitors for prevention and treatment of alzheimer's disease
US11752111B2 (en) * 2016-04-11 2023-09-12 GW Research Limited Use of cannabidivarin in the treatment of autism spectrum disorder, associated disorders and schizophrenia

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021189256A1 (fr) 2020-03-24 2021-09-30 中国医药大学 Utilisation de menthol pour la préparation d'une composition externe destinée à traiter une maladie neurodégénérative et un accident vasculaire cérébral

Cited By (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US10064850B2 (en) 2007-04-11 2018-09-04 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US20100234402A1 (en) * 2007-05-31 2010-09-16 Gideon Dreyfuss Methods and compositions for treating spinal muscular atrophy
GB2468828A (en) * 2008-01-04 2010-09-22 Gw Pharma Ltd Use of cannabinoids in combination with an anti-psychotic medicament
US9017737B2 (en) 2008-01-04 2015-04-28 Gw Pharma Limited Use of cannabinoids in combination with an anti-psychotic medicament
EP2609928A3 (fr) * 2008-01-04 2013-12-18 GW Pharma Limited Utilisation de cannabinoides en combinaison avec un medicament antipsychotique
EP3095452A1 (fr) * 2008-01-04 2016-11-23 GW Pharma Limited Utilisation de cannabidiol en combinaison avec de l'aripiprazole
WO2009087351A1 (fr) * 2008-01-04 2009-07-16 Gw Pharma Limited Utilisation de cannabinoïdes en combinaison avec un médicament antipsychotique
EP2609928A2 (fr) * 2008-01-04 2013-07-03 GW Pharma Limited Utilisation de cannabinoides en combinaison avec un medicament antipsychotique
GB2468828B (en) * 2008-01-04 2012-11-07 Gw Pharma Ltd Use of cannabinoids in combination with an anti-psychotic medicament
US8916132B2 (en) 2008-07-31 2014-12-23 Servicios Cientificos Neuroinnovation Ltda Benzimidazole-derived compounds use as markers in the case of neurodegenerative diseases
WO2010013127A1 (fr) * 2008-07-31 2010-02-04 Servicios Cientificos Neuroinnovation Ltda. Composés dérivés de benzimidazoles utiles en tant que marqueurs pour les maladies neurodégénératives
EP2327703A4 (fr) * 2008-08-22 2012-01-04 Ivashchenko Andrey Alexandrovich Ligand possédant une gamme étendue d activité pharmacologique, composition pharmaceutique, médicament et méthode de traitement
EP2327703A1 (fr) * 2008-08-22 2011-06-01 IVASHCHENKO, Andrey Alexandrovich Ligand possédant une gamme étendue d activité pharmacologique, composition pharmaceutique, médicament et méthode de traitement
US11389435B2 (en) 2008-09-15 2022-07-19 Biovista, Inc. Compositions and methods for treating epilepsy
US20110195049A1 (en) * 2008-10-13 2011-08-11 Biovista, Inc. Compositions and methods for treating multiple sclerosis
WO2010132810A1 (fr) * 2009-05-15 2010-11-18 Concert Pharmaceuticals, Inc. Benzimidazoles
EP2266550A1 (fr) * 2009-06-15 2010-12-29 Institut Curie Antagonistes de bêta-caténine pour la prévention et/ou le traitement des troubles neuro-dégénératifs
WO2011041731A3 (fr) * 2009-10-02 2011-06-16 Fred Hutchinson Cancer Research Center Procédé destiné à inhiber des protéines de survie apparentées aux bcl-2
US8865901B2 (en) 2009-10-02 2014-10-21 Fred Hutchinson Cancer Research Center Gain-of-function Bcl-2 inhibitors
ES2393499A1 (es) * 2009-11-23 2012-12-21 Laboratorios Del Dr. Esteve, S.A. Sales de duloxetina y AINE para el tratamiento del dolor
EP2332930A1 (fr) * 2009-11-23 2011-06-15 Laboratorios Del. Dr. Esteve, S.A. Sels de duloxétine et AINS pour le traitement de la douleur
WO2011060962A1 (fr) * 2009-11-23 2011-05-26 Laboratorios Del Dr. Esteve, S.A. Sels de duloxétine et nsaid pour le traitement de la douleur
WO2011107583A1 (fr) * 2010-03-04 2011-09-09 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 4-phényle-n-alkyle-pipéridines substituées destinées à prévenir le début ou à ralentir la progression de maladies neurodégénératives
US9856210B2 (en) * 2010-09-02 2018-01-02 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
US20130225642A1 (en) * 2010-09-02 2013-08-29 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
JP2017019776A (ja) * 2010-09-07 2017-01-26 イムンゲネテイクス・アーゲー β−アミロイドパシーまたはα−シヌクレオパシーを治療するための２−（Ｒ２−チオ）−１０−［３−（４−Ｒ１−ピペラジン−１−イル）プロピル］−１０Ｈ−フェノチアジン、およびβ−アミロイドパシーまたはα−シヌクレオパシーの診断または事前診断のための方法
EP2614060B1 (fr) * 2010-09-07 2016-08-31 Immungenetics AG Thiéthylpérazine pour le traitement d'une pathologie béta-amyloïde ou d'une alpha- synucléopathie
CN103237802A (zh) * 2010-09-07 2013-08-07 免疫基因股份公司 2-(R2-硫代)-10-[3-(4-R1-哌嗪-1-基)丙基]-10H-吩噻嗪用于治疗β-淀粉样病或α-共核蛋白病以及诊断或前诊断它们的方法
EP3097914A3 (fr) * 2010-09-07 2016-12-28 Immungenetics AG 2-(r²-thio)-10-[3-(4-r1-pipérazin-1-yl)propyl]-10h-phénothiazine pour le traitement d'une maladie neurodégénérative
CN106243060A (zh) * 2010-09-07 2016-12-21 免疫基因股份公司 2‑(R2‑硫代)‑10‑[3‑(4‑R1‑哌嗪‑1‑基)丙基]‑10H‑吩噻嗪用于治疗β‑淀粉样病或α‑共核蛋白病以及诊断或前诊断它们的方法
DE102010062810A1 (de) * 2010-09-07 2012-03-08 Universität Rostock 2-(R2-Thio)-10-[3-(4-R1-piperazin-1-yl)propyl]-10H-phenothiazine zur Behandlung neurodegenerativer Erkrankungen
JP2013537881A (ja) * 2010-09-07 2013-10-07 イムンゲネテイクス・アーゲー β−アミロイドパシーまたはα−シヌクレオパシーを治療するための２−（Ｒ２−チオ）−１０−［３−（４−Ｒ１−ピペラジン−１−イル）プロピル］−１０Ｈ−フェノチアジン、およびβ−アミロイドパシーまたはα−シヌクレオパシーの診断または事前診断のための方法
DE102010062810B4 (de) * 2010-09-07 2014-03-13 Immungenetics Ag 2-(R2-Thio)-10-[3-(4-R1-piperazin-1-yl)propyl]-10H-phenothiazine zur Behandlung neurodegenerativer Erkrankungen ausgewählt aus beta-Amyloidopathien und alpha-Synucleinopathien
CN103070876A (zh) * 2011-10-25 2013-05-01 中国农业科学院上海兽医研究所 一类抗乙型脑炎病毒感染的组合物及其应用
US10172854B2 (en) 2012-02-27 2019-01-08 Biovista, Inc. Compositions and methods for treating mitochondrial diseases
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy
EA027748B1 (ru) * 2012-04-04 2017-08-31 Тева Фармасьютикалз Интернэшнл Гмбх Применение придопидина в комбинации с тетрабеназином для лечения двигательных нарушений и ожирения
WO2013152105A1 (fr) 2012-04-04 2013-10-10 IVAX International GmbH Compositions pharmaceutiques pour traitement combiné
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
US11873266B2 (en) 2012-05-08 2024-01-16 Aeromics, Inc. Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke
WO2013179144A3 (fr) * 2012-06-01 2014-03-13 Oxalys Pharmaceuticals Suppresseurs chimiques de la neurotoxicité dans les maladies synucléinopathiques
US10525134B2 (en) 2012-06-05 2020-01-07 Neuroderm, Ltd. Compositions comprising apomorphine and organic acids and uses thereof
US9381249B2 (en) 2012-06-05 2016-07-05 Neuroderm, Ltd. Compositions comprising apomorphine and organic acids and uses thereof
US9999674B2 (en) 2012-06-05 2018-06-19 Neuroderm, Ltd. Compositions comprising apomorphine and organic acids and uses thereof
US9114130B2 (en) 2013-05-06 2015-08-25 University Of South Florida Compounds and related methods for treatment of neurodegenerative diseases
US10869831B2 (en) 2013-05-07 2020-12-22 Seelos Therapeutics, Inc. Treatment of protein aggregation myopathic and neurodegenerative diseases by parenteral administration of trehalose
US10751353B2 (en) * 2013-05-07 2020-08-25 Seelos Therapeutics, Inc. Compositions and methods for treating an aggregation disease or disorder
US9974860B2 (en) 2013-09-13 2018-05-22 Akiko Itai Aqueous solution formulation and method for manufacturing same
WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication
US11801254B2 (en) 2013-11-06 2023-10-31 Aeromics, Inc. Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US11071744B2 (en) 2013-11-06 2021-07-27 Aeromics, Inc. Prodrug salts
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US20160008320A1 (en) * 2014-07-14 2016-01-14 University Of Washington Statins in the treatment of muscular dystrophies and myopathies
US9974767B2 (en) * 2014-07-14 2018-05-22 University Of Washington Statins in the treatment of muscular dystrophies and myopathies
EP3034074A1 (fr) 2014-12-18 2016-06-22 Universitat De València, Estudi General Composé pour le traitement de la dystrophie myotonique de type 1
KR20170118870A (ko) * 2015-02-25 2017-10-25 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 질환을 치료하기 위한 5ht 작용제
KR102385665B1 (ko) 2015-02-25 2022-04-14 더 리젠츠 오브 더 유니버시티 오브 캘리포니아 질환을 치료하기 위한 5ht 작용제
JP2018506555A (ja) * 2015-02-25 2018-03-08 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 障害を治療するための５ｈｔ作動薬
WO2016138138A1 (fr) * 2015-02-25 2016-09-01 The Regents Of The University Of California Agonistes de récepteur 5ht pour le traitement de troubles
US10874643B2 (en) 2015-02-25 2020-12-29 The Regents Of The University Of California 5HT agonists for treating disorders
US11648237B2 (en) 2015-02-25 2023-05-16 The Regents Of The University Of California 5HT agonists for treating disorders
US10780149B2 (en) * 2015-04-24 2020-09-22 Consiglio Nazionale Delle Ricerche Therapeutic use of the botulinum neurotoxin serotype A
CN105078947A (zh) * 2015-08-07 2015-11-25 王红兵 他莫昔芬的用途
US11752111B2 (en) * 2016-04-11 2023-09-12 GW Research Limited Use of cannabidivarin in the treatment of autism spectrum disorder, associated disorders and schizophrenia
CN107375280B (zh) * 2016-05-17 2021-03-05 中国科学院上海药物研究所 硝唑尼特及其药学上可接受的盐在制备用于治疗阿尔茨海默病的药物中的应用
CN107375280A (zh) * 2016-05-17 2017-11-24 中国科学院上海药物研究所 硝唑尼特及其药学上可接受的盐在制备用于治疗阿尔茨海默病的药物中的应用
CN105924641A (zh) * 2016-06-06 2016-09-07 陕西省科学院酶工程研究院 一种硫酸羟基氯喹聚谷氨酸聚合物及其制备方法和应用
CN109414418A (zh) * 2016-06-29 2019-03-01 瓦伦塔有限责任公司 包含美金刚和褪黑素的组合的药物组合物
CN105920019B (zh) * 2016-07-05 2018-08-17 福州大学 一种含熊果酸与索拉菲尼的药物组合物及其在制备抗肿瘤药物中的应用
CN105920019A (zh) * 2016-07-05 2016-09-07 福州大学 一种含熊果酸与索拉菲尼的药物组合物及其在制备抗肿瘤药物中的应用
US10973890B2 (en) 2016-09-13 2021-04-13 Allergan, Inc. Non-protein clostridial toxin compositions
WO2018136600A1 (fr) 2017-01-20 2018-07-26 Teva Pharmaceuticals International Gmbh Utilisation de pridopidine pour traiter le syndrome de l'x fragile
US11234973B2 (en) 2017-01-20 2022-02-01 Prilenia Neurotherapeutics Ltd. Use of pridopidine for the treatment of fragile X syndrome
EP3570940A4 (fr) * 2017-01-20 2020-10-28 Prilenia Neurotherapeutics Ltd. Utilisation de pridopidine pour traiter le syndrome de l'x fragile
JP2020514313A (ja) * 2017-01-20 2020-05-21 プリレニア ニューロセラピューティクス リミテッド 脆弱ｘ症候群の治療のためのプリドピジンの使用
JP7114604B2 (ja) 2017-01-20 2022-08-08 プリレニア ニューロセラピューティクス リミテッド 脆弱ｘ症候群の治療のためのプリドピジンの使用
US11602538B2 (en) 2017-03-31 2023-03-14 The Florey Institute Of Neuroscience And Mental Health Prophylaxis and treatment of cognitive dysfunction and decline
WO2018176098A1 (fr) 2017-03-31 2018-10-04 The Florey Institute Of Neuroscience And Mental Health Prophylaxie et traitement d'un dysfonctionnement et d'un déclin cognitifs
EP3634410A4 (fr) * 2017-06-05 2021-03-03 The Methodist Hospital System Inhibiteurs de phosphorylation des protéines tau et méthodes de traitement ou de prévention de la maladie d'alzheimer
US11406625B2 (en) 2017-08-14 2022-08-09 Prilenia Neurotherapeutics Ltd. Method of treating amyotrophic lateral sclerosis with pridopidine
US11590093B2 (en) * 2018-04-13 2023-02-28 Healx Limited Kit, composition, and combination therapy for fragile X syndrome
WO2019241376A1 (fr) * 2018-06-14 2019-12-19 The Trustees Of Columbia University In The City Of New York Traitement de troubles cognitifs à l'aide de nitazoxanide (ntz), d'analogues de nitazoxanide (ntz) et de leurs métabolites
WO2021161319A1 (fr) * 2020-02-13 2021-08-19 Prilenia Neurotherapeutics Ltd. Polythérapie pour le traitement de la sclérose latérale amyotrophique à l'aide de pridopidine et d'un autre agent actif
EP4134363A1 (fr) * 2020-04-09 2023-02-15 Aventi Inc. Composition pharmaceutique pour la prévention ou le traitement de maladies associées à une faiblesse musculaire comprenant l'alvérine, 4-hydroxy alvérine ou un dérivé correspondant ou leur sel pharmaceutiquement acceptable
EP4134363A4 (fr) * 2020-04-09 2024-05-22 Aventi Inc. Composition pharmaceutique pour la prévention ou le traitement de maladies associées à une faiblesse musculaire comprenant l'alvérine, 4-hydroxy alvérine ou un dérivé correspondant ou leur sel pharmaceutiquement acceptable
CN114470215A (zh) * 2020-11-12 2022-05-13 北京科辉智药生物科技有限责任公司 Sarm1酶活性抑制剂及其在神经退行性疾病中的应用
CN112641784A (zh) * 2020-12-31 2021-04-13 南京中医药大学 一种具有治疗神经元损伤及/或神经炎症相关的神经退行性疾病作用的药物组合物
WO2023019823A1 (fr) * 2021-08-17 2023-02-23 南京中医药大学 Utilisation de desloratadine et de sel correspondant dans la préparation d'un médicament destiné au traitement de maladies neurodégénératives liées à un dysfonctionnement moteur
US20230233595A1 (en) * 2022-01-25 2023-07-27 New York Medical College Use of stat4 inhibitors for prevention and treatment of alzheimer's disease

Also Published As

Publication number Publication date
TW200848063A (en) 2008-12-16

Similar Documents

Publication Publication Date Title
WO2008133884A2 (fr) Procédés et compositions pour traiter des maladies neurodégénératives
US11246873B2 (en) Directed differentiation of oligodendrocyte precursor cells to a myelinating cell fate
CA2659956C (fr) Inhibiteurs de la pyruvate kinase et procedes de traitement de maladie
JP2018008981A (ja) パーキンソン病におけるジスキネジアを治療するための新規ｄ３ドーパミン受容体アゴニスト
DK3024458T3 (en) USE OF FLECAINID AS AN ANTI-CONNEXIN AGENT AND PROCEDURE FOR POTENSEING THE EFFECTS OF A PSYCHOTROTOPIC MEDICINE
US20110028564A1 (en) Compositions and methods for treatment of filovirus-mediated diseases
WO2005102366A2 (fr) Combinaisons de lithium et utilisations associees
Bortolozzi et al. In vivo modulation of 5‐hydroxytryptamine release in mouse prefrontal cortex by local 5‐HT2A receptors: effect of antipsychotic drugs
Gareri et al. Conventional and atypical antipsychotics in the elderly: a review
Waters et al. Pridopidine: overview of pharmacology and rationale for its use in Huntington’s disease
van Amsterdam et al. Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin 1A-receptor-mediated auto-augmentation of extracellular serotonin output
ES2295677T3 (es) Derivados de carboestirilo e inhibidores de la reabsorcion de serotonina para el tratamiento de trastornos del estado de animo.
Nackenoff et al. Serotonin transporter-independent actions of the antidepressant vortioxetine as revealed using the SERT Met172 mouse
Sergeeva et al. N-oleoyldopamine modulates activity of midbrain dopaminergic neurons through multiple mechanisms
US20060223857A1 (en) Combination of a serotonin reuptake inhibitor and a glycine transporter type 1 inhibitor for the treatment of depression
Minabe et al. Acute and chronic administration of clozapine produces greater proconvulsant actions than haloperidol on focal hippocampal seizures in freely moving rats
JP2007504181A (ja) セロトニン再取り込み阻害剤およびロキサピンの併用
JP2007513896A (ja) セロトニン再取り込み阻害剤およびヒスタミン３受容体アンタゴニスト、インバースアゴニストまたはパーシャルアゴニストの併用
JP2007513896A6 (ja) セロトニン再取り込み阻害剤およびヒスタミン３受容体アンタゴニスト、インバースアゴニストまたはパーシャルアゴニストの併用
Morissette et al. Trapping of adrenergic decongestant drugs into cellular endomembrane compartments: toxicological and pharmacological consequences
Taylor et al. A role for sigma binding in the antipsychotic profile of BMY 14802
KR20060072127A (ko) 세로토닌 재흡수 억제제 및 록사핀의 조합
Vaglenova et al. Behavioural Effects of the Interaction of 5-HT2/5HT1 Receptor Antagonist Dotarizine (DOT) and 5-HT3 Receptor Antagonist Ondansetron (OND) with Agonists and Antagonists of Other Subtypes of Receptors
US20080167290A1 (en) Combination of a Serotonin Reuptake Inhibitor and Amoxapine
US20060263299A1 (en) Effect of substances on sexual function

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08767406

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08767406

Country of ref document: EP

Kind code of ref document: A2